chr2-70935956-T-C

Variant names:

• chr2-70935956-T-C
• rs11681642
• NM_001692.4:c.2T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PVS1_Supporting BP6_Very_Strong BA1

The NM_001692.4(ATP6V1B1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 1,612,178 control chromosomes in the GnomAD database, including 148,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12699 hom., cov: 32)
  • Exomes 𝑓: 0.43 (135855 hom.)
• Consequence: ATP6V1B1 NM_001692.4 start_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.64
• Publications: 29 publications found

Genes affected

ATP6V1B1 (HGNC:853): (ATPase H+ transporting V1 subunit B1) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of two V1 domain B subunit isoforms and is found in the kidney. Mutations in this gene cause distal renal tubular acidosis associated with sensorineural deafness. [provided by RefSeq, Jul 2008]

VAX2 (HGNC:12661): (ventral anterior homeobox 2) This gene encodes a homeobox protein and is almost exclusively expressed in the ventral portion of the retina during development. In mouse studies, this gene was found to be required for the correct formation of the optic fissure and other aspects of retinal development. [provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 3 codons. Genomic position: 70935961. Lost 0.005 part of the original CDS.
• BP6: Variant 2-70935956-T-C is Benign according to our data. Variant chr2-70935956-T-C is described in ClinVar as Benign. ClinVar VariationId is 44228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001692.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	NM_001692.4	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 14	NP_001683.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	ENST00000234396.10	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 14	ENSP00000234396.4
	ATP6V1B1	ENST00000872157.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 14	ENSP00000542216.1
	ATP6V1B1	ENST00000872159.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 14	ENSP00000542218.1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61728 AN: 151874 Hom.: 12693 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.400 AC: 99661 AN: 249098 AF XY: 0.404

Gnomad AFR exome AF: 0.381

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.392

Gnomad FIN exome AF: 0.495

Gnomad NFE exome AF: 0.437

Gnomad OTH exome AF: 0.405

GnomAD4 exome AF: 0.429 AC: 625783 AN: 1460186 Hom.: 135855 Cov.: 36 AF XY: 0.427 AC XY: 310307 AN XY: 726338

African (AFR) AF: 0.374 AC: 12516 AN: 33450

American (AMR) AF: 0.267 AC: 11932 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 9716 AN: 26068

East Asian (EAS) AF: 0.372 AC: 14774 AN: 39664

South Asian (SAS) AF: 0.377 AC: 32504 AN: 86134

European-Finnish (FIN) AF: 0.490 AC: 26081 AN: 53228

Middle Eastern (MID) AF: 0.321 AC: 1849 AN: 5756

European-Non Finnish (NFE) AF: 0.442 AC: 491388 AN: 1110968

Other (OTH) AF: 0.415 AC: 25023 AN: 60312

GnomAD4 genome AF: 0.406 AC: 61755 AN: 151992 Hom.: 12699 Cov.: 32 AF XY: 0.409 AC XY: 30354 AN XY: 74272

African (AFR) AF: 0.379 AC: 15709 AN: 41456

American (AMR) AF: 0.316 AC: 4832 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1303 AN: 3464

East Asian (EAS) AF: 0.376 AC: 1944 AN: 5164

South Asian (SAS) AF: 0.357 AC: 1714 AN: 4806

European-Finnish (FIN) AF: 0.502 AC: 5314 AN: 10588

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29575 AN: 67910

Other (OTH) AF: 0.372 AC: 786 AN: 2112

Alfa AF: 0.423 Hom.: 37047

Bravo AF: 0.389

TwinsUK AF: 0.444 AC: 1648

ALSPAC AF: 0.447 AC: 1724

ESP6500AA AF: 0.373 AC: 1644

ESP6500EA AF: 0.437 AC: 3754

ExAC AF: 0.406 AC: 49326

Asia WGS AF: 0.337 AC: 1171 AN: 3478

EpiCase AF: 0.421

EpiControl AF: 0.421

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Renal tubular acidosis with progressive nerve deafness (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.6
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.83	P
Vest4		0.57
ClinPred		0.034	T
GERP RS		4.9
PromoterAI		0.025	Neutral
Varity_R		0.89
gMVP		0.60
Mutation Taster		=162/38	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11681642; hg19: chr2-71163086; COSMIC: COSV52265968; COSMIC: COSV52265968;